Obesity is now a world wide epidemic, and is one of the most serious contributors to increased morbidity and mortality. Obesity is prevalent in the United States, affecting more than 61% of the total population. One out of every three Americans is afflicted with obesity and another one third are overweight (Flegal, et al., Overweight and Obesity in the United States: Prevalence and Trends, 1960–1994. Int J Obes 22:39–47, 1998). Obesity is defined by the United States Centers for Disease Control and Prevention (CDC) as an excessively high amount of body fat or adipose tissue in relation to lean body mass and overweight as an increased body weight in relation to height, when compared to some standard of acceptable or desirable weight. The CDC alternatively defines overweight as a person with a body mass index (BMI) between 25.0 and 29.9 and obesity is defined as a BMI greater than or equal to 30.0. Obese and overweight mammals suffer from increased joint problems, increased rates of high blood pressure, and high cholesterol. Increased weight is also associated with heart disease, stroke and diabetes. In 1998, consumers spent $33 billion in the United States for weight-loss products and services with very little success (Serdula, et al., Prevalence of Attempting Weight Loss and Strategies for Controlling Weight, JAMA 282:1353–1358, 1999). Thus, obesity and its associated complications continue to be a major problem throughout the worldwide health care system.
Obesity is caused by both genetic and environmental factors. Genetic causes of this abnormality can result from a single gene mutation in animals, such as ob/ob mice, db/db mice, and obese fatty Zucker rats, but humans rarely develop obesity from a single gene mutation (Chaganon, et al., The Human Obesity Gene Map: The 1997 Update, Obes Res 6:76–92, 1998). Leptin deficiency from a single gene mutation was identified in ob/ob mice (Zhang, et al., Positional Cloning of the Mouse Obese Gene and its Human Homologue, Nature 372:425–432, 1994) and subsequently also in humans (Montague, et al., Congenital Leptin Deficiency is Associated With Severe Early-Onset Obesity in Human, Nature 387:903–908, 1997). Leptin deficiency is associated with hyperphagia, hyperinsulinemia, and insulin resistance (Prasad, et al., A Paradoxical Elevation of Brain Cyclo (his-pro) Levels in Hyperphagic Obese Zucker Rats, Brain Res 699:149–153, 1995). Administration of leptin reversed all of these symptoms. Leptin is produced exclusively in fat cells and the placenta, and blood-borne leptin signals the brain regarding quantities of stored fat by binding to the receptors in the hypothalamus. Leptin also interacts with the appetite and satiety centers in the brain to regulate body weight by balancing food intake and energy expenditures such as exercise and glucose metabolism (Halaas, et al., Weight-Reducing Effects of the Plasma Protein Encoded by the Obese Gene, Science 269:543–546, 1995). Leptin reduces hypothalamic neuropeptide Y (NPY) gene expression. (Schwartz, et al., Identification of Targets of Leptin Action in Rat Hypothalamus, J Clin Invest 98:1101–1106, 1996; Levine, et al., Neuropeptide Y: A Potent Inducer of Consummatory Behavior in Rats, Peptides 5:1025–1029, 1984). While ob/ob mice are deficient in leptin production, diabetic db/db mice and obese fatty Zucker rats have defective leptin receptor function. However, genetic abnormalities of leptin-receptor malfunction were not identified in human obesity (Considine, et al., Serum Immunoreactive-Leptin Concentrations in Normal Weight and Obese Humans, N Engl J Med 334:292–295, 1996). Most human obesity arises from increased food intake and decreased expenditure of energy (Bouchard, et al., The Response to Long-Term Overfeeding in Identical Twins, N Engl J Med 322:1477–1482, 1990). The surplus energy is stored as fat in adipose tissues. However, a variety of growth hormones, reproductive hormones, and many other factors influence fat formation (Fried, et al., Diverse Roles of Adipose Tissue in the Regulation of Systemic Metabolism and Energy Balance, In: Bray, G. A., Bouchard, C., James, W. P., eds. Handbook of Obesity, New York, Marcel Dekker, pp 397–414, 1977). The fat accumulation control system involves many different cellular processes, including energy expenditure, digestion, absorption, transport, and storage of nutrient fuels. Thus, it is extremely difficult to treat obesity by correcting a single biochemical pathway due to the contributions of multiple physiochemical abnormalities.
Drug treatment for obesity has been disappointing since almost all drug treatments for obesity were associated with undesirable side effects that contributed to their termination. Available pharmacotherapies have included Sibutramine, Orlistat, fenfluramine and dexfenfluramine. Fenfluramine and dexfenfluramine were withdrawn from the market in 1997 because of associated cardiac valvulopathy (Connolly, et al., Valvular Heart Disease Associated With Fenfluramine-Phentermine, New Engl J Med 337–581–588, 1997). Therefore, health care professionals continue to be reluctant to use pharmacotherapy in the management of obesity. Complimentary approaches to pharmacotherapy will therefore be of great interest to the public.
The better choice for treatment of obesity is to reduce food intake. A number of monoamines and neuropeptides are known to reduce food intake (Bray, et al., Pharmacological Treatment of Obesity, Am J Clin Nutr 55:151S–319S, 1992). Although body weight loss is effective, these sympathomimetic drugs cause side effects including pulmonary hypertension, neuroanatomic changes, and a typical valvular heart diseases. Thus, nutrition and dietary restriction are most desirable for weight loss. However, long-term success of dietary regulation is low because of noncompliance. The loss of motivation to change dietary habits necessary to consume less fat and fewer calories results in regaining weight.
Previous studies have indicated that prostaglandins (PGs) and arachidonic acid (AA), a precursor of prostaglandins, chelate zinc and regulate intestinal zinc absorption and secretion (Song et al., Am. J. Physiol. 234:E99 (1979); Song et al., J. Nutr. 109:2151 (1979); Koletzko et al., Eur. J. Pediatr. 143:310 (1985); Song et al., Prost. Leuko. Med. 17:159 (1984)). Isolated intestinal segments from diabetic rats showed significantly decreased intestinal zinc absorption capacity in Ussing chamber experiments (Song et al., Life Sci. 42:687 (1988)). When AA was added to the segment-bathing medium, zinc uptake increased significantly compared to controls. Although oral administration of low doses of AA decreased the intestinal zinc absorption rate, high doses of AA increased zinc absorption in non-diabetic rats (Song et al., Prost. Leuko. Med. 17:159 (1984)).
It has been reported that PGs and AA play important roles in the regulation of insulin release (Aalusha et al., “Prostaglandins and diabetes mellitus” in Diabetes Mellitus, Theory and Practice, ed. Ellenberg et al., pp. 295–308), and participate in numerous diabetes-related metabolic activities (Robertson, Med. Clin. 65:759 (1984); Katayama et al., Hypertension 7:554 (1985); Harrison et al., Diabetologia 18:65 (1980); Subbiah et al., Biochem. Med. 23:231 (1995); Johnson et al., Lancet 1:325 (1979); Shakir et al., J. Clin. Invest. 60:747 (1977); Goto et al., Diabetes 41:1644 (1992)).
Despite this background understanding, there still has not emerged an effective means of alleviating the symptoms associated with obesity by purposefully manipulating zinc metabolism in obese animals. New compositions and methods that fill this need are disclosed herein.